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p75NTR and DR6 Regulate Distinct Phases of Axon Degeneration Demarcated by Spheroid Rupture.

Authors
  • Yong, Yu1
  • Gamage, Kanchana2, 3
  • Cheng, Irene1, 4
  • Barford, Kelly4
  • Spano, Anthony1
  • Winckler, Bettina2
  • Deppmann, Christopher5, 4, 2, 6
  • 1 Department of Biology.
  • 2 Department of Cell Biology.
  • 3 Amgen, Massachusetts & Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts 02138.
  • 4 Neuroscience Graduate Program.
  • 5 Department of Biology, [email protected]
  • 6 Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia 22903, and.
Type
Published Article
Journal
Journal of Neuroscience
Publisher
Society for Neuroscience
Publication Date
Nov 27, 2019
Volume
39
Issue
48
Pages
9503–9520
Identifiers
DOI: 10.1523/JNEUROSCI.1867-19.2019
PMID: 31628183
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

The regressive events associated with trophic deprivation are critical for sculpting a functional nervous system. After nerve growth factor withdrawal, sympathetic axons derived from male and female neonatal mice maintain their structural integrity for ∼18 h (latent phase) followed by a rapid and near unison disassembly of axons over the next 3 h (catastrophic phase). Here we examine the molecular basis by which axons transition from latent to catastrophic phases of degeneration following trophic withdrawal. Before catastrophic degeneration, we observed an increase in intra-axonal calcium. This calcium flux is accompanied by p75 neurotrophic factor receptor-Rho-actin-dependent expansion of calcium-rich axonal spheroids that eventually rupture, releasing their contents to the extracellular space. Conditioned media derived from degenerating axons are capable of hastening transition into the catastrophic phase of degeneration. We also found that death receptor 6, but not p75 neurotrophic factor receptor, is required for transition into the catastrophic phase in response to conditioned media but not for the intra-axonal calcium flux, spheroid formation, or rupture that occur toward the end of latency. Our results support the existence of an interaxonal degenerative signal that promotes catastrophic degeneration among trophically deprived axons.SIGNIFICANCE STATEMENT Developmental pruning shares several morphological similarities to both disease- and injury-induced degeneration, including spheroid formation. The function and underlying mechanisms governing axonal spheroid formation, however, remain unclear. In this study, we report that axons coordinate each other's degeneration during development via axonal spheroid rupture. Before irreversible breakdown of the axon in response to trophic withdrawal, p75 neurotrophic factor receptor-RhoA signaling governs the formation and growth of spheroids. These spheroids then rupture, allowing exchange of contents ≤10 kDa between the intracellular and extracellular space to drive death receptor 6 and calpain-dependent catastrophic degeneration. This finding informs not only our understanding of regressive events during development but may also provide a rationale for designing new treatments toward myriad neurodegenerative disorders. Copyright © 2019 the authors.

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